Chromosome 9p21 Research Articles

206 Spinal Meningioma: An Institutional Case Series With Preliminary Results of Molecular Profiling

INTRODUCTION: Spinal meningiomas have historically been considered similar entities to intracranial meningiomas, but recent developments in molecular profiling have identified unique features. METHODS: Retrospective study of patients undergoing resection of spinal meningioma between 2010–2022 at our institution. Patient, radiographic, and clinical characteristics were reviewed and analyzed with standard statistical methods. Molecular profiling was conducted on three tumors. RESULTS: A total of 33 tumors were resected in 26 patients. Median follow-up was 39.5 (0–149) months. Twenty-five (89.3%) procedures were in female patients. The median age at surgery was 62 (18–84) years. The median tumor was 1.9 (0.9–9) cm. Six tumors (18.2%) were in the cervical region, 28 (48.5%) were thoracic, and 2 (6.1%) were lumbar. Sixteen (48.5%) tumors were located dorsally, 11 (33.3%) ventrally, and six (18.2%) extended dorsoventrally. Gross total resection was achieved in 25 (75.8%) tumors. Median progression-free survival was 139 months. On histological analysis of 28 tumors, 26 (92.9%) were WHO grade 1 and 2 (7.1%) were WHO Grade 3 with a median Ki-67 of 3 (1–20)%. Fourteen (50.0%) tumors were psammomatous, seven (25%) were meningothelial, two (7.1%) were anaplastic, and one was transitional. Molecular profiling was available for three tumors. All three were negative for TERT promoter mutations and exhibited loss of chromosome 22. Chromosomal microarray analysis also detected gains in chromosomes 3p, 9, 11, 12, and 20 and loss of chromosomes 16 and 19 in Tumor 1. Tumor 3 also showed loss of chromosomes 12p and X, with copy-neutral loss of heterozygosity affecting chromosomes 5q, 7q, and 14q. CONCLUSIONS: Preliminary molecular profiling studies of spinal meningiomas show features distinct from intracranial meningiomas, so there is a need for their further molecular characterization.

Smith-Magenis Syndrome associated with Autism Spectrum Disorder with delayed diagnosis due to B12 deficiency: a case report

IntroductionSmith-Magenis syndrome (SMS) is a complex genetic disorder characterised by distinctive physical features, developmental delay, cognitive impairment and a typical behavioural phenotype. SMS is caused by interstitial 17p11.2 deletions (90%) involving multiple genes, including the retinoic acid-induced 1 gene (RAI1), or by pathogenic variants in RAI1 itself (10%).ObjectivesIn this case report, we present a case of Smith-Magenis syndrome with Autism Spectrum Disorder with karyotype 46,XX, 17p 11.2 gene deletion confirmed by Autism Spectrum Disorder, who was followed up in a paediatric neurology outpatient clinic with neuromotor developmental delay and whose diagnosis was delayed due to B12 deficiency. We also update scientific developments in Smith-Magenis syndrome.MethodsWe describe an 18-month-old male with Smith-Magenis syndrome and Autism Spectrum Disorder who was seen in our paediatric psychiatric outpatient clinic and who received B12 replacement with developmental delay.ResultsThe patient was followed up in the paediatric neurology outpatient clinic with delay in neuromotor developmental milestones and this delay was thought to be due to B12 deficiency (B12<100 ng/L). The initial examination revealed delay in neuromotor and behavioural milestones, speech delay, wide and high nasal bridge and hypertelorism. Further physical examination revealed syndactyly of the second and third toes bilaterally and crossed lower teeth. Clinical and psychometric testing (Ankara Developmental Screening Inventory) by 2 consultants and 1 research assistant resulted in a diagnosis of intellectual disability and an additional diagnosis of Autism Spectrum Disorder due to social deficits that could not be explained by intellectual disability.ConclusionsSmith-Magenis syndrome is a well-known disorder involving the deletion of chromosome 17p11.2, which contains the RAI1 gene. This condition is associated with neuromotor and behavioural delay, as well as distinctive dysmorphic features. Clinicians should consider Smith-Magenis syndrome in the differential diagnosis for patients with delayed neuromotor and behavioural milestones, even in the presence of documented blood parameters (such as B12 deficiency) that may account for the delay.Disclosure of InterestNone Declared

Huge mesenchymal hamartoma in a young adult: a case report

Abstract Mesenchymal hamartoma of the liver (MHL) is rare. Less than 50 adult cases have been described. Due to their potential degeneration or recurrence, a complete surgical resection must be performed. We describe a case of a 26-year-old with a palpable solid lesion, which displaced abdominal organs. Percutaneous needle biopsies suggested the diagnosis of MHL. A right hemi-hepatectomy without segment 1 was performed; the post-operative course was uneventful. The mesenchymal component of the tumour was reactive to desmin and smooth muscle actin. Low proliferation index was confirmed (MIB1). Genetic counselling: the sequencing analysis of DICER1 and CDKN1C gene was negative, DNA methylation analysis on the chromosome 11p15 region was normal. After 42 months, there was no recurrence. In conclusion, clinicians should consider MHL in the differential diagnosis. The dimension and the need of radicality impose major liver resections or liver transplantations, which should be performed in referral centres.

Huntington’s disease: A comprehensive case report

Chorea form movements, neuropsychiatric symptoms, and cognitive impairment are hallmarks of Huntington's disease, an inherited progressive neurodegenerative illness that results in severe functional impairment. Between the ages of 30 and 40, it typically shows up. The genetic components of the disease are inherited, meaning that the afflicted individual receives the gene from a parent with the same genetic makeup. It is inherited in an autosomal-dominant manner. It is brought on by increased cytosine-adenine-guanine (CAG) tri-nucleotide repeat in Huntington’s (HTT) gene on chromosome 4p. A patient with a strong family history of Huntington's disease is described, associated with their clinical and genetic features.

The gut metabolite indole-3-propionic acid activates ERK1 to restore social function and hippocampal inhibitory synaptic transmission in a 16p11.2 microdeletion mouse model

BackgroundMicrodeletion of the human chromosomal region 16p11.2 (16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document}) is a prevalent genetic factor associated with autism spectrum disorder (ASD) and other neurodevelopmental disorders. However its pathogenic mechanism remains unclear, and effective treatments for 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} syndrome are lacking. Emerging evidence suggests that the gut microbiota and its metabolites are inextricably linked to host behavior through the gut-brain axis and are therefore implicated in ASD development. Despite this, the functional roles of microbial metabolites in the context of 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} are yet to be elucidated. This study aims to investigate the therapeutic potential of indole-3-propionic acid (IPA), a gut microbiota metabolite, in addressing behavioral and neural deficits associated with 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document}, as well as the underlying molecular mechanisms.ResultsMice with the 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} showed dysbiosis of the gut microbiota and a significant decrease in IPA levels in feces and blood circulation. Further, these mice exhibited significant social and cognitive memory impairments, along with hyperactivation of hippocampal dentate gyrus neurons and reduced inhibitory synaptic transmission in this region. However, oral administration of IPA effectively mitigated the histological and electrophysiological alterations, thereby ameliorating the social and cognitive deficits of the mice. Remarkably, IPA treatment significantly increased the phosphorylation level of ERK1, a protein encoded by the Mapk3 gene in the 16p11.2 region, without affecting the transcription and translation of the Mapk3 gene.ConclusionsOur study reveals that 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} leads to a decline in gut metabolite IPA levels; however, IPA supplementation notably reverses the behavioral and neural phenotypes of 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} mice. These findings provide new insights into the critical role of gut microbial metabolites in ASD pathogenesis and present a promising treatment strategy for social and cognitive memory deficit disorders, such as 16p11.2 microdeletion syndrome.92Bbfs5rK2Gd_SbL4an2CwVideo

Study the Association between TP53 (rs12602273C>G) Gene Polymorphism with Susceptibility to the Breast Cancer in North West of Iran

Introduction: The TP53 gene on the short arm of chromosome 17p, which is known as a tumor suppressor gene, encodes the transcription factor p53, and this factor controls cell cycle progression. This study was done to assess the association of TP53 (rs12602273C>G) gene polymorphism with the risk and prognosis of breast cancer in women of northwest of Iran.
 Methods: In this case-control study, the association of TP53 (rs12602273C>G) gene polymorphism with breast cancer risk was studied in a population, including 100 patients and 100 healthy individuals was investigated by Tetra ARMS-PCR technique. The analysis of the resulting data was done using SPSS version 16 software and JavaStat online statistics package.
 Results: In the case group, the frequency of CC, CG, and GG genotypes were 81.52, 16.3, 2.17 percent, respectively and they were 79.34, 17.39, and 3.26 percent for the control group. Similarly, C and G allele frequency in case group was 89.67 and 10.32 percent and those in the control group was 88.04 and 11.95 percent, respectively. Statistical analyzes showed no association between genotypic (P>0.05) and allelic (P>0.05) polymorphism (rs12602273C>G) of TP53 gene with breast cancer. Also, the results showed that the studied polymorphism was not associated with the clinical characteristics of breast cancer patients in the Northwest of Iran (P>0.05).
 Conclusion: These research findings suggest that TP53 polymorphism of rs12602273C>G is not related to the risk of breast cancer. The association of the genotypic distribution of this SNP with the clinical characteristics of the patients was insignificant.

Microbiota profiling reveals alteration of gut microbial neurotransmitters in a mouse model of autism-associated 16p11.2 microduplication.

The gut-brain axis is evident in modulating neuropsychiatric diseases including autism spectrum disorder (ASD). Chromosomal 16p11.2 microduplication 16p11.2dp/+ is among the most prevalent genetic copy number variations (CNV) linked with ASD. However, the implications of gut microbiota status underlying the development of ASD-like impairments induced by 16p11.2dp/+ remains unclear. To address this, we initially investigated a mouse model of 16p11.2dp/+, which exhibits social novelty deficit and repetitive behavior characteristic of ASD. Subsequently, we conducted a comparative analysis of the gut microbial community and metabolomic profiles between 16p11.2dp/+ and their wild-type counterparts using 16S rRNA sequencing and liquid chromatography-mass spectrometry (LC/MS). Our microbiota analysis revealed structural dysbiosis in 16p11.2dp/+ mice, characterized by reduced biodiversity and alterations in species abundance, as indicated by α/β-diversity analysis. Specifically, we observed reduced relative abundances of Faecalibaculum and Romboutsia, accompanied by an increase in Turicibacter and Prevotellaceae UCG_001 in 16p11.2dp/+ group. Metabolomic analysis identified 19 significantly altered metabolites and unveiled enriched amino acid metabolism pathways. Notably, a disruption in the predominantly histamine-centered neurotransmitter network was observed in 16p11.2dp/+ mice. Collectively, our findings delineate potential alterations and correlations among the gut microbiota and microbial neurotransmitters in 16p11.2dp/+ mice, providing new insights into the pathogenesis of and treatment for 16p11.2 CNV-associated ASD.

Особенности патологии органа зрения при орфанном синдроме Pierson вследствие мутации гена LAMB2 у детей: обзор литературы и клиническое наблюдение

Pierson syndrome is an orphan disease with an autosomal recessive mode of inheritance, characterized by combined pathology of the organ of vision, kidneys and central nervous system. Pierson syndrome is caused by a mutation in the LAMB2 gene, mapped on chromosome 3p21, encoding β2-laminin. The pathology of the organ of vision in Pierson syndrome in children is quite diverse. They are characterized by the presence of cataract, posterior lenticonus, iris hypoplasia, glaucoma, retinal detachment, etc. Microcoria (pupil diameter less than 2 mm) is also often observed due to atrophy of the pupillary dilator. The final diagnosis of Pierson syndrome can only be made based on the results of a molecular genetic study. Due to the severe lifethreatening renal manifestations of Pierson syndrome, for a long time the description of ophthalmological pathology was rather superficial. However, considering the high frequency and clinical severity of vision pathology in Pierson syndrome, it seems especially important to study in detail the features of the ocular phenotype in this disease. We have described a clinical observation of a child with Pierson syndrome, who was diagnosed with a missense mutation of the LAMB2 gene, a previously undescribed variant (rs143405268) in exon 18. The disease manifested itself as a combined pathology of the organ of vision, kidneys and the central nervous system. The ocular phenotype of the probands represented by microcoria, diffuse congenital cataract, and later by secondary glaucoma (after cataract surgery). Features of the renal phenotype of the proband were revealed – a horseshoe-shaped kidney, proteinuria not reaching the level of nephrotic syndrome, with preserved renal function. The peculiarity of this case of a child with Pierson syndrome is the absence of nephrotic syndrome in combination with the classic ocular phenotype with a previously undescribed variant of the LAMB2 gene mutation identified. Key words: pierson syndrome, LAMB 2, congenital cataract, microcoria, secondary glaucoma

Family case of Potocki-Lupski syndrome

BackgroundPotocki-Lupski syndrome (PTLS, OMIM # 610883) is a rare genetic developmental disorder resulting from a partial heterozygous microduplication at chromosome 17p11.2. The condition is characterized by a wide variability of clinical expression, which can make its clinical and molecular diagnosis challenging.Case presentationWe report here a family (mother and her two children) diagnosed with PTLS. When examining children, neurological and psychological (neuropsychiatric) manifestations (speech delay, mild mental retardation), motor disorders, craniofacial dysmorphism (microcephaly, dolichocephaly, triangular face, wide bulging forehead, long chin, antimongoloid slant, "elfin" ears) were revealed. The suspected clinical diagnosis was confirmed by MLPA and CMA molecular genetic testing which revealed the presence of a segmental aneusomy; microduplication in the 17p11.2 region.ConclusionsChildren with PTLS can have a clinically recognizable and specific phenotype: craniofacial dysmorphism, motor and neurological manifestations, which may implicate a possible genetic disease to the attending physician. Moreover, each child with this syndrome is unique and may have a different clinical picture. The management of such patients requires a multidisciplinary team approach, including medical genetic counseling.

Abstract 4598: Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers

Abstract Homozygous deletions of the p16/CDKN2a (cyclin dependent kinase inhibitor 2A) locus, which is responsible for regulating the cell cycle, are commonly found in cancer and often involve the deletion of adjacent genes. One such adjacent gene is methylthioadenosine phosphorylase (MTAP), involved in metabolism, located on chromosome 9p21 in close proximity to the p16/CDKN2A tumor-suppressor locus. Co-deletion of MTAP is observed in approximately 80-90% of tumors with homozygous deletion of CDKN2A, representing 10-15% of all human tumors. These tumor types, including non-small cell lung cancer, pancreatic adenocarcinoma, glioblastoma, and mesothelioma, have a poor prognosis, highlighting the significant unmet medical need in this area. Deletion of MTAP leads to a significant accumulation of methylthioadenosine (MTA) in cells. MTA, at high concentrations, selectively inhibits the PRMT5 methyltransferase enzyme, competing with the substrate S-adenosylmethionine (SAM) required for methylation reactions. As a result, the overall level of symmetric arginine dimethylation throughout the proteome is reduced. This heightened sensitivity to modulation of methylosome activity makes cells with MTAP deletion more susceptible to therapeutic targeting of PRMT5. Hence, selective targeting of PRMT5 in cancers with homozygous MTAP deletion represents a promising strategy for specifically eliminating cancer cells with this genetic alteration. Ryvu has developed MTA-cooperative PRMT5 inhibitors characterized by good drug-like physicochemical properties and inhibition of methyltransferase activity with IC50 values in the low nanomolar range. A structure-based lead optimization delivered compounds coming from two independent series with high selective potency in MTAP-deleted cell lines and DMPK profiles allowing an oral administration. The antitumor activities were compared in vitro and in vivo to MRTX1719 and AMG193 in MTAP null tumors such as HCT116 MTAP KO, DoHH-2 and Lu99. The correlation between compound exposure and on-target effect was confirmed in PK/PD and efficacy studies. Taken together, these studies confirm that MTA cooperative PRMT5 inhibitors exert strong synthetic lethal phenotype in MTAP deleted cancers and offer an exciting therapeutic opportunity for a large patient population. Citation Format: Adam Radzimierski, Aneta Bobowska, Agata Stachowicz, Kamil Kuś, Kamila Kozłowska-Tomczyk, Agnieszka Ludwig-Słomczyńska, Paulina Podkalicka-Gołda, Aniela Gołas, Monika Żukowska, Pavlo Lebed, Przemysław Wyrębek, Daria Szukiel, Matylda Stefaniak, Oleksandr Popika, Julia Krzywik, Sujit Sasmal, Paulina Niedziejko-Ćwiertnia, Klara Korta-Piątek, Karolina Fijołkowska, Aleksandra Więckowska, Marta Olszak-Płachta, Swapnil Nipunge, Mateusz Świrski, Marek Wronowski, Henryk Pawlik, Quỳnh Vũ, Katarzyna Łagosz-Ćwik, Mateusz Stoszko, Szymon Woroszyło, Igor Tomczyk, Ewelina Gabor-Worwa, Nilesh Gaud, Anna Kowal-Chwast, Dawid Gogola, Magdalena Miodek, Róża Starczak, Agata Dudek, Jacek Faber, Bożena Winnik, Sanja Novak-Ratajczak, Agnieszka Świrska, Karolina Gluza, Paweł Guzik, Katarzyna Banaszak, Nicolas Boutard, Grzegorz Ćwiertnia, Krzysztof Brzózka, Mateusz Nowak, Anna Bartosik, Didier Pez. Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4598.

Abstract 4636: Genome-wide drug anchor screens identify CAAP1 and AKAP17A as regulators of PRMT5 inhibitor sensitivity

Abstract MTA-cooperative PRMT5 inhibitors are an emerging treatment option for patients with one of the 10-15% of all human cancers harboring MTAP homozygous deletion. To identify potential regulators of sensitivity to PRMT5 inhibitors, we performed genome-wide CRISPR knockout screens in the presence and absence of an MTA-cooperative PRMT5 inhibitor. Knockout of CAAP1 and AKAP17A were among the strongest sensitizing hits across multiple MTAP-deleted cancer cell lines representing different histologies. Strikingly, the CAAP1 gene co-localizes with MTAP and CDKN2A on chromosome 9p21. Co-deletion of CAAP1 is reported in 20 percent of MTAP-deleted cancers in the TCGA PanCancer Atlas. CAAP1 or AKAP17A knockout in MTAP-deleted cancer cell lines sensitized the cells to PRMT5 inhibitors including the clinical stage MTA-cooperative inhibitors, TNG908 and TNG462, and the non-MTA-cooperative inhibitor, GSK3326595. Moreover, we discovered that CAAP1 and AKAP17A protein levels are interdependent, as knockout of either gene caused decreased protein levels for the other. Consistent with this finding, CAAP1 reconstitution in CAAP1-deleted cell lines led to increased AKAP17A levels. Endogenous CAAP1 and AKAP17A protein levels are positively correlated across a panel of cancer cell lines and MTAP-deleted patient-derived xenograft models. Consistent with a previous report (Ni et al., 2023), exogenous CAAP1 and AKAP17A co-immunoprecipitation studies suggest that the proteins form a protein complex. AKAP17A and CAAP1 are not well-characterized proteins, but PRMT5 inhibitors induce global alternative splicing events (ASEs) in cancer cells, and based on preliminary studies a possible function for the CAAP1/AKAP17A complex could be to mitigate ASEs induced by PRMT5 inhibition. Collectively, these data indicate that CAAP1 and AKAP17A exist interdependently and mediate sensitivity to PRMT5 inhibitors. The colocalization and 20 percent incidence of CAAP1 deletion in the setting of MTAP deletion may suggest that such patients will have improved responses to PRMT5-targeted therapy. S. Yoda and M. R. Tonini contributed equally. Citation Format: Satoshi Yoda, Matthew R. Tonini, Hilary E. Nicolson, Samuel Poleretzky, Silvia Fenoglio, Steven Lombardo, Lauren Grove, Samuel R. Meier, Ashley Choi, Yi Yu, Kevin M. Cottrell, John P. Maxwell, Teng, Jannik N. Andersen, Kimberly J. Briggs. Genome-wide drug anchor screens identify CAAP1 and AKAP17A as regulators of PRMT5 inhibitor sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4636.

Abstract 3634: Copy number alterations in chromosome 19 genes associate with reduced immune infiltrate and adverse outcomes in lung cancer

Abstract Deleterious mutations in STK11/LKB1, KEAP1, and SMARCA4 have been shown to be associated with adverse response to immunotherapy in several lung cancer cohorts. However, the biological and clinical implications of deletions of these genes, which all reside on chromosome 19p (chr19p), has not been extensively described. We sought to first characterize the association between immune infiltration and these copy number changes in chr19p. To do this, we analyzed mutation, copy number, and gene expression data from non-small cell lung cancer cohorts in the Cancer Genome Atlas (TCGA). Chr19p is frequently deleted across cancers in the TCGA dataset, with higher rates in lung adenocarcinoma. In both lung adenocarcinoma and squamous cell carcinoma, nearly half of TCGA tumors have deletion of chr19p including STK11, KEAP1, and SMARCA4, and these tumors are enriched for STK11 mutation. Immune infiltrate (estimated by methylation patterns) was not significantly associated with STK11 mutation but was significantly reduced in tumors with chr19 deletion when controlling for tumor type and overall copy number load. In addition, low-level deletion of any of these genes correlated with decreased expression of immune signaling pathways. Based on these findings, we next wanted to characterize the association between chr19p copy number and immunotherapy response. We previously reported that low-level deletion of STK11 correlated with an immunosuppressive, treatment-refractory phenotype in samples collected from non-small cell lung cancer (NSCLC) patients with resectable disease in a phase II study of neoadjuvant atezolizumab + chemotherapy. To confirm these findings in a larger cohort, we examined the AACR GENIE NSCLC biopharma collective (BPC) dataset. A subset of this cohort included patients treated with immunotherapy (atezolizumab, nivolumab, and/or pembrolizumab) and with copy number data available or GISTIC analysis of individual genes (n = 204). Here, deletion of any of these three genes correlated with worse overall survival, and this was statistically significant for STK11 deletion. Overall, our data suggests that a broader set of patients, defined by copy number changes in these genes, may experience this adverse immunobiology. Further study to elucidate the mechanistic implications of this association is warranted. Citation Format: Brian S. Henick, Yohanna Georgis, Benjamin O. Herzberg, Carla P. Concepcion-Crisol, Alison M. Taylor. Copy number alterations in chromosome 19 genes associate with reduced immune infiltrate and adverse outcomes in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3634.

Abstract 7295: A novel XNA technology-based assay to detect JAK2 V617F mutation by real-time PCR

Abstract The Janus kinase 2 (JAK2) gene is located on chromosome 9p24.1 and encodes a non-receptor tyrosine kinase that plays a central role in cytokine and growth factor signaling. The JAK2 protein is especially important for controlling the production of blood cells from hematopoietic stem cells. In fact, the JAK2 mutation at amino acid 617 (Valine 617 to Phenylalanine, V617F) is the most frequently detected mutation in myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). This dominant gain-of-function V617F mutation results in constitutive tyrosine phosphorylation activity, leading to uncontrolled blood cell production, including increased numbers of erythrocytes, neutrophils, and platelets. To detect the JAK2 V617F mutation in DNA from patient blood samples, we developed a unique real-time PCR assay using our proprietary XNA technology that enables the assay to selectively amplify the mutant sequence by using a synthetic DNA analog XNA (Xenonucleic Acid). The JAK2 V617F mutation detection assay is designed to detect a valine-to-phenylalanine mutation at amino acid 617 (V617F). PCR primers, TaqMan probes, and XNA were designed for the JAK2 V617F mutation, along with primers and probes for an internal control gene in the duplex setting. The analytical performance of the assay was verified and validated using a variety of control samples. The results revealed that the XNA completely suppressed the amplification of wildtype sequence while only the V617F mutant sequence was amplified. The JAK2 V617F mutation detection assay is highly reproducible with intra- and inter-assay coefficients of variation of less than 10%. Results for the assay’s analytical sensitivity indicated that V617F could be detected with about 0.25% mutant allele frequency in 10 ng DNA input. In addition, no significant cross-amplification between V617F and V617I was observed. Thus, the JAK2 V617F mutation detection assay is specific for the V617F mutation. The JAK2 V617F mutation detection assay, using XNA-based technology, provides high sensitivity and specificity to detect the JAK2 V617F mutation. Thus, this assay would be a useful tool for clinical decision-making in determining the presence of the JAK2 V617F mutation in DNA from patient blood samples. Citation Format: Shuo Shen, Robert Brown, Daniel Kim, Larry Pastor, Andrew Y. Fu, Pushpinder Kaur, Alisha Babu, Wei Liu, Aiguo Zhang, Hiromi Tanaka, Michael Y. Sha. A novel XNA technology-based assay to detect JAK2 V617F mutation by real-time PCR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7295.

Abstract 3364: PELO is a synthetic lethal target in chromosome 9p21-deleted or MSI cancers

Abstract Homozygous deletion of chromosomal region 9p21.3 is one of the most frequently observed somatic copy number alterations in cancers, occurring in approximately 15% of all cancers. Many of the 9p21.3-deleted cancers are further characterized by poor clinical outcomes including subsets of glioblastoma, pancreatic, esophageal, and urothelial cancers. Large deletions of chromosomal regions may also provide unique therapeutic opportunities. Specifically, cancer-specific therapeutic opportunities can arise from co-deletions of passenger genes neighboring tumor suppressors. As such, we sought to identify novel therapeutic targets associated with Ch9p21.3 loss in cancers and identified the pelota mRNA surveillance and ribosome rescue factor (PELO) as the top preferential dependency in 9p21.3-deleted cancers. Intriguingly in another analysis, we identified PELO to be amongst the top preferential dependencies in cancers with microsatellite instability (MSI), which accounts for subsets of colorectal, endometrial, gastric, and ovarian cancers. Given the strength of PELO as a candidate synthetic lethal target in two distinct cancer subsets, we performed focused validation with CRISPR interference across multiple cell lines. Knockdown of PELO preferentially impaired the viability of MSI or 9p21-deleted as compared to control (9p21-proficient and microsatellite stable) cells. Further validation with patient-derived organoid and in vivo xenograft models confirmed these findings. We next sought to refine the predictive biomarkers for PELO dependency and identified loss of FOCAD (a 9p21.3 gene and an interactor of the SKI mRNA surveillance pathway) as necessary and sufficient for PELO dependency in the 9p21.3-deleted context. Our findings implicate splicing alterations involving TTC37, a key protein in the SKI mRNA surveillance complex, as the underlying cause of PELO dependency in MSI cancers. Together, we found that loss of large deletions of 9p21.3 and MSI independently impair the SKI complex, uncovering a dependency upon PELO and highlighting a novel functional interaction between PELO and the SKI complex. Furthermore, the strength of this synthetic lethal interaction in a broad range of cancers with poor outcomes underscores the potential of PELO as a promising drug target for patients with 9p21.3-deleted or MSI cancers. Citation Format: Edmond M. Chan, Patricia Borck, Nolan Bick, Kristina Jankovic, Isabella Boyle, Lucy Parker-Burns, Kyla Foster, Anthony Lau, Ashir Borah, Joshua Dempster, Francisca Vazquez. PELO is a synthetic lethal target in chromosome 9p21-deleted or MSI cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3364.

Abstract 7610: Predictive biomarkers for immuno-chemotherapy response in biliary tract malignancies

Abstract Background: Biliary tract cancers (BTCs) refer to invasive malignancies of the biliary tree. Lack of specific symptoms in early-stages frequently leads to late-stage diagnosis, reducing therapeutic options. Surgical resection remains the only curative option for early-stage disease; instead, patients with advanced disease usually receive chemotherapy (cisplatin plus gemcitabine) in combination with durvalumab as first-line treatment and mFOLFOX-6 as second-line, but effects are limited and only a small proportion of patients respond to treatment. Recent advances in molecular characterization of BTCs allowed the identification of several alterations (e.g. IDH1/2 mutations, FGFR2 rearrangement) for which targeted agents are now available in second line setting but only for a small subset of patients. However, prognosis for patients with advanced stage disease remains poor. Treatment failure depends on several factors such as intra- and inter-tumor heterogeneity and the complex immunological landscape. Therefore, the identification of predictive biomarkers able to individuate patients that will benefit from immuno-chemotherapy will be crucial. Methods: BTC patients at any stage were enrolled in two arms: A) BTCs undergoing surgery; B) advanced/relapsed BTCs. For this study, patients belonging to arm B were selected, in particular those who received first-line immuno-chemotherapy. Blood samples were collected before and after three months of therapy. Ascites samples were collected for patients with advanced disease who underwent paracentesis during therapy. DEPArray NxT (Menarini Silicon Biosystems) was used for phenotypic analysis and single ascites-derived cell isolation. The Ampli1 Lowpass kit was used for copy number aberration (CNA) profiling. Extracellular vesicles (EVs) were isolated from plasma at baseline and after three months of immuno-chemotherapy by size-exclusion chromatography and analyzed for size distribution and concentration using Nanosight NS300. Surface EV markers were analyzed by flow cytometry using the MACSPlex Exosome Kit human (MiltenyiBiotec). Results: We enrolled 43 patients starting from August 2022: 14 in arm A and 29 in B. 23 patients from arm B received immuno-chemotherapy and 3 underwent paracentesis during therapy. Patient-derived organoids (PDOs) were successfully established from tumor cells recovered from ascites of these patients. Epithelial cells recovered from ascites displayed aberrant CNA profiles with gains in chromosomes 1q, 8q, 10, 12p, 20, and losses in 1q, 3q, 4, 8q, 9 and X. EV size distribution and concentration were similar before and after treatment as well as surface markers exposure. Further analyses in correlation with clinical features of patients will be performed. Conclusions: Our approach will contribute to identify potential predictive factors associated with response/resistance to immuno-chemotherapy in BTCs. Citation Format: Michele Zanoni, Tania Rossi, Martina Valgiusti, Giuliano La Barba, Michela Cortesi, Sara Bandini, Giulia Bartolini, Alessandra Dubini, Paolo Di Gioia, Chiara Gallio, Luca Esposito, Alessandra Virga, Giorgia Gurioli, Sara Bravaccini, Giovanni Martinelli, Paola Ulivi, Giovanni Luca Frassineti, Giorgio Ercolani, Ilario Giovanni Rapposelli. Predictive biomarkers for immuno-chemotherapy response in biliary tract malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7610.

Abstract 5211: Somatic copy number variation as prognostic marker for recurrence in never-smokers with early-stage lung adenocarcinoma

Abstract Objective: Lung cancer in never-smokers has a distinct genomic profile with low tumor mutation burden, more tumor promotor mutations and fewer somatic copy number variations (CNV) than smokers. CNVs have shown to be associated with poor outcome in advanced stage disease. However, the relationship between CNV and clinicopathologic features on prognosis in early-stage lung cancer is undefined. To address this knowledge gap, we assessed the impact of CNV on recurrence in never-smokers who underwent curative resection for pathological stage I-II lung adenocarcinoma using an integrated genomic and clinicopathological analysis. Methods: We analyzed a cohort of 210 never-smokers with stage I-II lung adenocarcinoma treated from 2014 to 2022 who met the inclusion criteria (no neoadjuvant therapy, pathological stage I-II, complete resection, next-generation sequencing available). The patient cohort was stratified using unsupervised hierarchical clustering of arm-level CNVs. We assessed cumulative incidence of recurrence (CIR) between CNV groups using competing risk regression analysis, adjusting for SUVmax, pathologic stage, lymphovascular invasion, IASLC grade, and tumor mutation burden. Results: Of the 210 patients, 159 patients were female (76%), and patients were primarily from Caucasian (n=140, 67%) or Asian decent (n=50, 24%). Based on arm-level CNV clustering, the cohort was stratified into three groups: CNV low (n=86, 41%), CNV moderate (n=75, 36%) and CNV high (n=49, 23%). The CNV low tumors were characterized by a low CNV burden. Conversely, the CNV moderate tumors primarily exhibited gains in chromosomes 1q, 5p and 7p, along with loss of heterozygosity in chromosome 9p, 9q and 13. CNV high tumors were characterized by whole-genome doubling. Whole-genome doubling was significantly more common in CNV high tumors (n=33, 66%) compared to CNV low (n=2, 2.3%) and CNV moderate tumors (n=2, 2.7%) (p<.001). EGFR (n=145, 69%) and TP53 (n=61, 29%) were the most frequently altered genes, with EGFR alterations being significantly more prevalent in CNV high tumors (n=41, 84%) compared to CNV low tumors (n=46, 53%) (p<.001). In total, 42 patients (20%) developed recurrences. The CIR was lower in the CNV low group (5y-CIR, 14%, 95%CI: 6.5%-25%) compared to the CNV moderate (5y-CIR, 31%, 95%CI: 18%-44%) and CNV high group (5y-CIR, 48%, 95%CI: 27%-66%) (p=.004), with adjusted hazard ratios of 2.3 (95%CI: 0.93-5.71; p=0.074) and 2.65 (95%CI: 1.07-6.60; p=.037), respectively. The CIR for locoregional (n=11, 5%) and distant recurrence (n=31, 15%) remained lower in the CNV low group compared to the combined CNV moderate & high groups (Gray test p=.020 and p=.049, respectively). Conclusion: In never-smokers who underwent curative treatment of pathological stage I-II lung adenocarcinoma, copy number status seems a predictor of recurrence, with CNV low tumors associated with the best prognosis. Citation Format: Stijn Vanstraelen, Allison Reiner, Brooke H. Mastrogiacomo, Kay See Tan, Joseph Dycoco, Bernard J. Park, Prasad S. Adusumilli, Matthew J. Bott, David R. Jones, Gaetano Rocco. Somatic copy number variation as prognostic marker for recurrence in never-smokers with early-stage lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5211.

Beckwith–Wiedemann syndrome with juvenile fibrous nodules and lobular breast tumors: a case report and review of the literature

BackgroundBeckwith–Wiedemann syndrome (BWS) is a genomic imprinting disorder caused by diverse genetic and/or epigenetic disorders of chromosome 11p15.5. BWS presents with a variety of clinical features, including overgrowth and an increased risk of embryonal tumors. Notably however, reports of patients with BWS and breast tumors are rare, and the association between these conditions is still unclear. Insulin-like growth factor-2 (IGF2) expression is known to be associated with the development of various cancers, including breast cancer, and patients with BWS with specific subtypes of molecular defects are known to show characteristic clinical features and IGF2 overexpression.Case presentationA 17-year-old girl who had been diagnosed with BWS based on an umbilical hernia, hyperinsulinemia, and left hemihypertrophy at birth, visited our department with a gradually swelling left breast. Her left breast was markedly larger than her right breast on visual examination. Imaging examinations showed two tumors measuring about 10 cm each in the left breast, and she was diagnosed with juvenile fibroadenoma following core needle biopsy. The two breast tumors were removed surgically and the patient remained alive with no recurrence. The final diagnosis was juvenile fibroadenoma without malignant findings. Immunohistochemical staining using IGF2 antibody revealed overexpression of IGF2 in the cytoplasm of ductal epithelial cells. Because of her clinical features and IGF2 overexpression, molecular defects of 11p15.5 including a possible genetic background of paternal uniparental disomy of chromosome 11 or hypermethylation of imprinting center 1 was suspected.ConclusionsIn this case, overexpression of IGF2 suggested a possible relationship between BWS and breast tumors. Moreover, the characteristic clinical features and IGF2 staining predicted the subtype of 11p15.5 molecular defects in this patient.

Abstract 6144: A polymorphic TERT tandem repeat creating an expandable intronic G4 quadruplex is associated with TERT expression, relative leukocyte telomere length and cancer risk

Abstract A multi-cancer GWAS region at human chromosome 5p15 encodes telomerase reverse transcriptase (TERT). One of the GWAS signals is rs10069690-T, which creates an alternative intron 4 splicing site, co-producing full-length (FL) and truncated INS1b transcript for dominant-negative telomerase-nonfunctional TERT. A variable number tandem repeat (VNTR6-1, 38 bp repeat unit) within intron 6 remains uncharacterized in relation to GWAS signals and cancer risk. We hypothesized that VNTR6-1 might contribute to GWAS signals represented by rs10069690. We scored VNTR6-1 and rs10069690 in short-read WGS data (n=3,202) from the 1000 Genomes Project with a machine learning model using the GLMnet engine, and in phased long-read assemblies (n=544). We defined two VNTR6-1 groups: Short (24-27 copies) and Long (40.5-66.5 copies); the VNTR6-1-Long group was preferentially linked with rs10069690-T compared to C allele (p=2.53E-13). We show that haplotypes of rs56345976 and rs33961405 alleles can predict VNTR6-1 groups. We imputed VNTR6-1 in UK Biobank controls (n=351,634), PLCO cancer cases and controls (n=100,445), and African Burkitt lymphoma cases (aBL, n=79). Functional studies in aBL tumors revealed a suggestive association between reduced total TERT expression, rs10096690-T (p=0.035) and VNTR6-1-Long (p=0.053). VNTR6-1 forms a G4 quadruplex structure sensitive to G4 stabilizing ligands, altering the ratio between FL-TERT and a dominant-negative TERT-β isoform in isogenic cell lines with/without VNTR6-1. In GTEx and TCGA, several metrics related to cell proliferation and telomerase activity correlated positively with FL-TERT expression and negatively with TERT-β expression. We created a composite marker with 0, 1 or 2 copies of the FL-TERT-associated haplotype (VNTR6-1-Short/rs10069690-C) to capture the effects of these variants that negatively affect TERT expression and telomerase activity. The number of copies of the VNTR6-1/rs10069690 haplotype was associated with relative leukocyte telomere length in UK Biobank controlling for sex and age (β=0.049, p=8.75E-78). This marker was also associated with a reduced risk of bladder and prostate cancer but an increased risk of breast, endometrial, ovarian, thyroid cancer, and glioma in PLCO. Our findings reveal that germline variants VNTR6-1-Long/rs10069690-T underlie the multi-cancer GWAS signal and jointly decrease TERT expression and telomerase activity, potentially reducing the risk of some cancers by limiting cell growth. However, decreased telomerase activity could deregulate stem cell-driven tissue regeneration and genome integrity, increasing the risk of other cancers. Our findings unveil novel mechanisms of cancer susceptibility and propose therapeutic avenues for targeting TERT isoform ratios to modulate telomerase activity and its cellular effects. Citation Format: Oscar Florez-Vargas, Michelle Ho, Max Hogshead, Chia-Han Lee, Kaitlin Forsythe, Brenen Papenberg, Kristine Jones, Wen Luo, Kedest Teshome, Cornelis Blauwendraat, Mikhail Kolmogorov, Stephen J. Chanock, Mitchell J. Machiela, John Schneekloth, Shahinaz Gadalla, Sharon A. Savage, Sam M. Mbulaiteye, Ludmila Prokunina-Olsson. A polymorphic TERT tandem repeat creating an expandable intronic G4 quadruplex is associated with TERT expression, relative leukocyte telomere length and cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6144.

Abstract 6929: Inter- and intratumoral PIK3CA subclonal diversity in breast cancer contextualized by single-cell multiomics

Abstract Rare clonotypes within pre-cancerous tissues can drive progression to cancer. However, the evolution of rare clonotypes in tumors or normal tissue cannot be defined in the absence of single-cell resolution. At this single-cell level, multiomic interrogation across the Central Dogma of Biology provides enhanced power to reconstruct such evolutionary trajectories, defining the mutational profile, cell identify, and receptor expression within each subpopulation. Leveraging a multiomic approach, we aimed to define how different mutations in the same oncogenic driver observed in the same tumor resection associate with copy number variation (CNV) across the genome. We analyzed individual ductal carcinoma in situ/invasive ductal carcinoma cells using a unified whole-genome and full-transcript RNAseq workflow (ResolveOME™, BioSkryb Genomics) coupled with panel-level extracellular protein information through oligo-conjugated antibodies (BioLegend). We sequenced the exomes and transcriptomes of ResolveOME-amplified single cells from mastectomy samples from twelve patients. At the single nucleotide variant (SNV) level, we identified an allelic series of PIK3CA oncogenic driver mutations in the same tumor resection. A single amino acid, in-frame deletion of E109 dominated the sample, followed by H1047R and K111E in decreasing subclonal abundance. A fourth mutation, E345T, not present in the first sample, was detected as the sole PIK3CA variant in the second tumor sample. Intriguingly, each respective PIK3CA mutation class was associated with a distinct copy number alteration profile revealed by low-coverage whole-genome sequencing: Cells harboring the predominant ΔE109 mutation displayed chromosome 8p,16p, and 17 loss while the less abundant H1047R mutation was in single cells harboring 1q gain, 4q loss, and 22 loss in addition to the 8p and 16q loss present in the ΔE109 cells. PIK3CA K111E had a quiescent, 2n copy number profile. The transcriptomic arm of ResolveOME, containing an oligo-conjugated antibody readout of surface protein expression, jointly confirmed the epithelial identity for the cells harboring the oncogenic PIK3CA mutations. A subpopulation of cells harboring prototypical breast cancer CNV were typed as non-epithelial with increased stemness characteristics, indicative of the ability to resolve phenotypic cellular states. These results suggest a tight interrelationship between CNV and SNV influencing the relative rate of clonal expansion. They also provide the opportunity to explore CNV:SNV signature association with loci exclusive of PIK3CA, and to exploit the power of multiomic integration for lineage reconstruction and for defining common oncogenic signatures of the evolving tumors. Citation Format: Jon Zawistowski, Isai Salas-Gonzalez, Tia Tate, Tatiana Morozova, Katherine Kennedy, Durga Arvapalli, Jamie Remington, Jeffrey Marks, E. Shelley Hwang, Gary Harton, Victor Weigman, Jay A. West. Inter- and intratumoral PIK3CA subclonal diversity in breast cancer contextualized by single-cell multiomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6929.

Abstract 5047: Identifying genomic features associated with pathologic lymph node metastasis in lung adenocarcinoma patients

Abstract Introduction: Lymph node metastasis evaluation in solid tumors is mainly complicated by the diagnostic yield of standard imaging modalities and tumor size contradictions. Exploring clinical/molecular features that complement the use of radiologic and bronchoscopy findings may provide significant values for a more accurate pathologic determination of nodal metastasis. Methods: We analyzed surgery-resected tumor samples from 72 treatment-naïve lung adenocarcinoma (LUAD) patients via whole-exome sequencing (WES). Mutational profiles of patients categorized based on their pathologic lymph node metastasis (pN) status were assessed, and the association between metastatic-driving features and overall survival (OS) was then explored in both the study cohort and the Cancer Genome Atlas Program (TCGA) external cohort. Results: Among all 72 patients, 41 (56.9%) were pathologically confirmed as positive for lymph node metastasis (pN-positive), while 31 (43.1%) were categorized as pN-negative. The most frequently mutated gene was TP53 in both subgroups (54.8% and 53.7%, respectively), and the aberrant KEAP1-NRF2 signaling pathway was found significantly more enriched in pN-negative patients. Copy-number variant analysis showed that chromosome 7p amplifications (X7p_amp) at the arm level and EGFR amplifications at the focal gene level were more frequently identified in pN-positive patients (P=0.008 and P=0.004, respectively). Importantly, these amplifications were associated with worse OS in both the study cohort and the TCGA external dataset. Consistent with the unfavorable prognosis, pN-positive patients demonstrated a higher chromosome instability score (CIS) (median: 0.32 vs. 0.14, P=0.14) and a lower tumor mutation burden (TMB) (median: 1.83 vs. 3.85 muts/Mb, P=0.048) compared to pN-negative patients. Conclusion: Our findings suggest that X7p_amp, particularly EGFR amplification, might be associated with pathologic involvement of lymph nodes and an unfavorable prognosis in LUAD patients. Our study highlights the importance of integrating clinical and genomic data into conventional radiologic modalities for a more accurate determination of pathologic nodal involvement. Citation Format: Shijie Wang, Zhiwei Zhou, Song Wang, Rongyun Guo, Zeming Ma, Dachuan Zhao, Liang Wang, Yinan Liu, Yuanyuan Ma, Jianzhi Zhang, Sha Wang, Yedan Chen, Haimeng Tang, Qiuxiang Ou, Jinfeng Chen. Identifying genomic features associated with pathologic lymph node metastasis in lung adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5047.